1. Field of the Invention
Melampomagnolide B (3) is disclosed as a new antileukemic sesquiterpene. A biotin-conjugated derivative (4) of melampomagnolide B was prepared to elucidate its mechanism of action. A study of the biochemical interactions of the biotin probe suggests that melampomagnolide B derives its remarkable selectivity for leukemic cells over normal hematopoietic cells from its unique ability to exploit biochemical differences between the two cell types. Prodrugs of Melampomagnolide B are disclosed.
2. Description of the Related Art
The past several years have seen a surge of interest in the anticancer properties of sesquiterpene lactones. A germacrenolide, parthenolide (PTL, 1) has been noted for its remarkable antileukemic properties. Skalska et al. PLoS ONE, 2009, 4, e8115. Initial efforts pertaining to the biomechanistic study of parthenolide and its analogs revealed that they seem to promote apoptosis by inhibiting the activity of the NF-kB transcription factor complex, and thereby down-regulating anti-apoptotic genes under NF-kB control. Bork et al. FEBS Lett. 1997, 402, 85; Wen, J. Biol. Chem., 2002, 277, 38954; Hehner et al., J. Biol. Chem. 1998, 273, 1288; Sweeney et al., Clin. Cancer Res., 2004, 10, 5501; Yip-Schneider et al., Mol. Cancer. Ther., 2005, 4, 587; Nozaki et al., Oncogene, 2001, 20, 2178. Nuclear factor kB (NF-kB) is a transcriptional regulator that plays a central part in responses to inflammatory signaling.

Parthenolide induces robust apoptosis of primary acute myeloid leukemic (AML) cells. Guzman et al., Blood, 2005, 105, 4163; Guzman and Jordan, Exp. Opin. Biol. Ther., 2005, 5, 1147. In particular, parthenolide causes cell death in AML stem and progenitor cells in vitro, with minimal toxicity towards normal hematopoietic cells. The apoptosis induced by parthenolide is not solely due to NF-kappaB inhibition, but rather arises from a broad set of biological responses, which likely include activation of p53 and an increase in reactive oxygen species. Parthenolide has also been the source of several novel antileukemic compounds arising from our program over the past decade. For example, parthenolide analogs were prepared by adding amines to the exocyclic olefin of the enone function of 1, thereby rendering the resulting compounds water-soluble. Neelakantan et al., Bioorg. Med. Chem. Lett., 2009, 19, 4346; Nasim and Crooks, Bioorg. Med. Chem. Lett., 2008, 18, 3870. Such adducts showed retention of antileukemic properties of parthenolide; in particular, the dimethylamine-adduct of parthenolide (DMAPT, LC-1, 2), which has progressed to phase-I clinical trials in the United Kingdom for the treatment of AML, ALL and CLL. Neelakantan et al., 2009.
Unfortunately, DMAPT has a relatively short in vivo half-life (approximately two hours) which may limit its activity. Moreover, the design of this molecule does not readily afford opportunities to develop tissue-targeting strategies due to stability problems associated with drug formulation. This is related to the ability of the drug to undergo reverse Michael deamination reactions to generate parthenolide. Thus, there is a need to both improve the biological activity of PTL and create novel pharmacological agents with drug-like characteristics that can be formulated as oral dosage forms.
One PTL analog that was synthesized via selenium oxide oxidation was a C10 hydroxymethyl derivative. Notably, hydroxylation of the C10 methyl group of PTL resulted in the concomitant conversion of the geometry of the C9-C10 double bond from trans to cis. The resulting product, a hydroxymethyl 1(10)-cis-parthenolide analog, has previously been reported as melampomagnolide B (MMB). Melampomagnolide B (MMB, 3) is a melampolide originally isolated from Magnolia grandiflora. El-Feraly, Phytochemistry, 1984, 23, (10); 2372-2374.
It is herein disclosed that melampomagnolide B (MMB, 3) has been identified as a new antileukemic sesquiterpene with properties similar to parthenolide (PTL, 1). Further, as a functionalized analog of PTL, the MMB molecule allows the synthesis of conjugated analogs that retain biological activity.